1. Field of the Invention
This invention relates to nutrient compositions for use in clinical nutrition and more particularly, to nutrient compositions containing certain dipeptides.
2. Description of the Prior Art
Proteins are converted to amino acids in the digestive system and the resulting amino acids are used by the body for growth and development. In certain medical situations a patient may be unable to receive proteins. In these situations patients have been given free amino acids. Free amino acids, however, are sometimes not tolerated well by patients and may cause diarrhea and dehydration.
It has been observed that the body can more effectively absorb certain small molecules called dipeptides or tripeptides. In particular, it has been observed that peptides containing the amino acid residue glycine in the N-terminal position are readily assimilable. U.S. Pat. No. 4,340,592 (hereinafter Adibi I). Adibi I requires glycine to be the peptide in the N-terminal position because "glycine-terminated oligopeptides achieve a desirable intact transport of the oligopeptide into a cell. The glycine grouping protects the oligopeptide from hydrolysis into amino acids by the peptidases on a cell membrane . . . The glycine grouping is also lipophilic and the oligopeptide has an enhanced transport through the cell membrane . . . The glycine terminated oligopeptides are particularly water-soluble which permits the use of such oligopeptides in high concentration." Col. 2, 11. 35-55.
It was later found, however, that if glycine-terminated oligopeptides are the only peptide in the nutrient solution, excess glycine may develope.
European Patent Application No. 0,182,356 (hereinafter Adibi II) discloses a nutritional composition containing at least one oligopeptide consisting of a dipeptide or a tripeptide wherein the N-terminal amino acid residue is glycine residue and at least one oligopeptide consisting of a dipeptide or a tripeptide wherein the N-terminal amino acid residue is selected from the class consisting of alanine, lysine and arginine. The oligopeptide concentration is from 0.2 to 30 weight percent. For total parenteral nutrition, the preferred range is from 5 to 15 weight percent of the oligopeptide. The total protein nutrients in the compositions are from 2 to 40 weight percent. These prior teachings suggest the use of amino acids having high solubility in water, such as glycine (25.0 grams/100 ml 25.degree. C.), as the N-terminal amino acid in the oligopeptide.
Adibi et al. conclude that glycine is generally superior to other amino acids as the N-terminal amino acid residue in a dipeptide because a greater fraction of such an intravenously administered dipeptide reaches the tissues. S. Adibi et al., Influence of Molecular Structure on Half-life and Hydrolysis of Dipeptides in Plasma: Importance of Glycine as N-Terminal Amino Acid Residue, 35 Metabolism 850, 835 (1986).
Another group that is studying nutrient compositions including dipeptides is Pfrimmer & Co. Two European patents, 0,087,751, hereinafter Pfrimmer I and 0,087,750 (Pfrimmer II) disclose water-soluble peptides. Pfrimmer I discloses a method to parenterally administer low water-soluble amino acids. Two amino acids, tyrosine and cystine, individually have low solubility in water. These amino acids, however, are clinically useful. The disclosed infusion method involves bonding these difficultly soluble amino acids to the two amino groups of the amino acid lysine to produce a tripeptide.
Pfrimmer II discloses the infusion of glutamine as a derivative substituted by .alpha.-aminoacyl residues on the .alpha. amino group. That is, glutamine is in the "c-terminal" position, in that its alpha amino nitrogen becomes part of the peptide bond with the other amino acid. The preferred dipeptide preparation disclosed in Pfrimmer II is alanyl-glutamine. The aminoacylation of glutamine is reported to achieve a stabilization of the terminal amide group.
Experiments involving the use of total parenteral nutrition containing glycyl-glutamine dipeptides, however, suggest the potential adverse effect of the TPN formulation containing glycyl-glutamine. In this experiment slightly preterm, colostrum-deprived piglets were maintained on total parenteral nutrition from birth to day 7 of life. All piglets in this study have been enrolled and completed the study period in the University of Florida Piglet Neonatal Intensive Care Unit. Ten piglets in the control group received standard neonatal piglet total parenteral nutrition solution containing amino acids, glucose, lipid, vitamins and minerals. Eleven piglets in the experimental group received the same total perenteral nutrition formulation with the exception that 20% of the amino acids in the standard solution was replaced with glutamine. Since the glutamine was in the form of a dipeptide, administration of 1 gram of glutamine required the coadministration of approximately 0.5 gram of glycine. Nine piglets in each group completed the full 7 days of the study. One piglet in the control group and two piglets in the experimental group became septic. The two septic piglets in the experimental group exhibited signs of severe convulsions while the septic piglet in the control group exhibited no signs of convulsions.
To date, the amino acid analyses have been completed on blood samples from six of the piglets in the experimental group and on blood samples from seven of the piglets in the control group. The plasma amino acid data listed below indicate that administration of the glycylglutamine dipeptide increases the plasma glutamine concentrations in the piglets in the experimental group compared to the concentrations measured in plasma from the piglets in the control group.
______________________________________ PLASMA GLUTAMINE CONCENTRATIONS CONTROL PIGLETS EXPERIMENTAL PIGLETS Piglet nmol/ml Piglet nmol/ml ______________________________________ P253 215 P260 709 P259 189 P263 805 P262 358 P266 646 P265 384 P269 415 P268 255 P272 272 P271 240 P275 417 P274 266 MEAN: 544 MEAN: 272 ______________________________________
Based on the problems associated with the above discussed peptides, an alternate method to deliver low water-soluble, and potentially toxic amino acids, such as glutamine, is needed.